Infections with oncogenic types of HPV cause virtually all cases of cervical cancer worldwide. Prophylactic vaccination against HPV 16 and 18, two of the most important HPV types, could protect against a large majority of the cases of cervical cancer globally. Vaccines based on the L1 structural protein of HPV that self-assemble into conformationally-correct virion-like particles (virus-like particles or VLPs) are under study. The immunogenicity and safety of HPV 16 & 18 VLPs have been demonstrated in Phase 1 and Phase 2 human trials. Evidence from Phase 3 trial interim analyses also suggest high efficacy of VLP-based vaccines in protecting against type-specific persistent HPV infection and associated lesions. Two VLP-based vaccines have been developed; one has recently been approved for use. The second is expected to be approved for use in the near future. A full-scale Phase 3 randomized controlled trial of an HPV16/18 VLP vaccine has been initiated in Costa Rica. Costa Rica was chosen for the Phase 3 trial because of our extensive successful scientific collaborations there, the continued high risk of cervical cancer, the universal medical system providing national linkage, and the likelihood of very high participation over the many needed years of close clinical follow-up. Randomization and 3-dose vaccination of 7,466 women enrolled into the HPV-16/18 Vaccine Trial in Costa Rica has been successfully completed. Four years of active follow-up are underway for each participant. Should the vaccine be proven to be safe and effective, and to provide protection against HPV infection for several years, cross-over vaccination will be offered to trial participants. This cross-over will occur after four years of follow-up are compelted for each woman, if recommended by the trial Data and Safety Monitoring Board (DSMB) and approved by the Institutional Review Boards (IRBs) overseeing the trial. To date, the trial remains masked. A primary analysis of the prophylactic effect of this vaccine is planned and will be triggered at the end of 4-years of follow-up or when sufficient numbers of events occur to warrant evaluation. Evaluation of the therapeutic benefit of this vaccine has been completed. Results from the analysis indicate that the vaccine does not have any effect on clearance of HPV infections, when administered to women who already have an established infection. Thus, the vaccine should not be used to treat established HPV infections or their associated lesions. In support of the vaccine trials, a variety of methodologic and ancillary projects are underway or planned, that will maximize the yield of the main effort.